Regioselective Suzuki-Miyaura reactions of the bis(triflate) of 1,2,3,4-tetrahydro-9,10-dihydroxyanthracen-1-one

Article abstract of DOI:10.1016/j.tetlet.2010.11.052

The palladium(0)-catalyzed Suzuki cross-coupling reaction of the bis(triflate) of 1,2,3,4-tetrahydro-9,10-dihydroxyanthracen-1-one afforded various aryl-substituted 1,2,3,4-tetrahydroanthracen-1-ones. The reactions proceeded with very good site-selectivit

Full text of DOI:10.1016/j.tetlet.2010.11.052

Tetrahedron Letters 52 (2011) 392–394
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Regioselective Suzuki–Miyaura reactions of the bis(triflate) of
1,2,3,4-tetrahydro-9,10-dihydroxyanthracen-1-one
Ghazwan A. Salman a, Ahmed Mahal a, Mohanad Shkoor a, Munawar Hussain a, Alexander Villinger a,
Peter Langer a,b,
⇑
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The palladium(0)-catalyzed Suzuki cross-coupling reaction of the bis(triflate) of 1,2,3,4-tetrahydro-9,10-
dihydroxyanthracen-1-one afforded various aryl-substituted 1,2,3,4-tetrahydroanthracen-1-ones. The
reactions proceeded with very good site-selectivity in favour of position 10, due to electronic reasons.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 18 October 2010
Revised 8 November 2010
Accepted 9 November 2010
Available online 20 November 2010
Keywords:
Catalysis
Anthracenones
Palladium
Suzuki–Miyaura reaction
Regioselectivity
Functionalized 1,2,3,4-tetrahydroanthracen-1-ones are of con-
siderable pharmacological relevance and occur in various natural
products.1 Examples include the pigments atrochrysone and
torosachrysone, isolated from fungi as well as higher plants, which
represent key intermediates of the biosynthesis of polyketide-
derived pigments (Fig. 1).2 In fungi (genus Cortinarius), they serve
as biosynthetic precursors of a large number of anthraquinone
pigments.3 A variety of anthracenones have also been reported to
possess potent cytotoxic and anticancer activities.4–7 For example,
olivomycin A is a famous anthracenone and a member of the aure-
OH OH O
O
OH
HO
OH
H
H
OH
OH
OMe
Olivin
OH OH O
4-hydroxy-a-tetralone
OH OH O
Me
Me
OH
olic acid family of antitumor antibiotics. 4-Hydroxy-a-tetralones
MeO
OH
HO
act as inhibitors of PTP1B and are considered potential
drugs against obesity and type-2 diabetes. In addition, anthrace-
nones are potentially interesting because of their photochemical,
photonic, and electronic properties.
Atrochrysone
Torosachrysone
Figure 1. Tetralone and anthracenone natural products.
Because of potential applications in medicinal or materials
chemistry, the development of synthetic approaches to new
anthracenone derivatives is of current interest. In recent years,
site-selective palladium(0) catalyzed reactions of polyhalogenated
substrates have gained increasing importance.8 In this context,
Suzuki–Miyaura reactions of bis(triflates) have also been
developed.9 Herein, we report a new and convenient approach to
aryl-substituted 1,2,3,4-tetrahydroanthracen-1-ones by Suzuki–
Miyaura reactions of the bis(triflate) of 1,2,3,4-tetrahydro-9,10-
dihydroxyanthracen-1-one. The reactions proceed with very good
site-selectivity which is controlled by electronic parameters. The
synthesis of the products reported herein has, to the best of our
knowledge, not been previously described. It can be anticipated
that they are not readily available by other methods.
1,2,3,4-Tetrahydro-9,10-dihydroxyanthracen-1-one (1) was
transformed into bis(triflate) 2 in 85% yield (Scheme 1).10
The Suzuki–Miyaura reaction of 2 with boronic acids 3a–f
(2.4 equiv) afforded the novel 1,2,3,4-tetrahydro-9,10-diarylan-
thracen-1-ones 4a–f in 70–90% yields (Scheme 2, Table 1). The best
yields were obtained when Pd(PPh3)4 (6 mol %) was used as the
⇑
Corresponding author. Fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.052

G. A. Salman et al. / Tetrahedron Letters 52 (2011) 392–394
393
Table 2
Synthesis of 5a–g
OTf
OH
i
3
5
Ar
% (5)a
a
b
c
d
h
i
a
b
c
d
e
f
4-(MeO)C6H4
4-EtC6H4
4-ClC6H4
4-MeC6H4
4-tBuC6H4
3-CF3C6H4
2,6-Me2C6H3
75
74
70
87
75
73
88
OTf
O
OH
O
2 (85%)
1
Scheme 1. Synthesis of 2. Reagents and conditions: (i) CH2Cl2, 1 (1.0 equiv), À78 °C,
pyridine (4.0 equiv), Tf2O (2.4 equiv), À78 °C ? 20 °C, 14 h.
j
g
a
Yields of isolated products.
OTf
OTf
Ar
ArB(OH)2
3a-f
OTf
Ar2
1) Ar1B(OH)2
2) Ar2B(OH)2
O
Ar
O
4a-f
2
i
Ar1
O
Scheme 2. Synthesis of 4a–f. Reagents and conditions: (i)
2
(1.0 equiv), 3a–f
OTf
O
(2.2 equiv), Pd(PPh3)4 (6 mol %), K3PO4 (3.0 equiv), 1,4-dioxane, 120 °C, 10 h.
2
6a-f
Scheme 4. Synthesis of 6a–f. Reagents and conditions: (i) 2 (1.0 equiv), 3a,c,d,h,i
(1.0 equiv), Pd(PPh3)4 (3 mol %), K3PO4 (3 equiv), 1,4-dioxane, 100 °C, 10 h; (ii)
3a,d,f,h (1.1 equiv), Pd(PPh3)4 (3 mol %), 120 °C, 10 h.
Table 1
Synthesis of 4a–f
3,4
Ar
% (4)a
Table 3
Synthesis of 6a–f
a
b
c
d
e
f
4-(MeO)C6H4
4-EtC6H4
4-ClC6H4
4-MeC6H4
4-FC6H4
3-ClC6H4
75
80
72
85
70
74
90
3
6
Ar1
Ar2
% (6)a
a,h
c,h
c,a
h,d
i,d
a
b
c
d
e
f
4-(MeO)C6H4
4-ClC6H4
4-ClC6H4
4-tBuC6H4
3-CF3C6H4
4-MeC6H4
4-tBuC6H4
4-tBuC6H4
4-(MeO)C6H4
4-MeC6H4
4-MeC6H4
3-ClC6H4
77
75
70
80
68
70
g
3,5-Me2C6H3
a
Yields of isolated products.
d,f
a
Yields of isolated products.
catalyst, when 2.4 equiv of the boronic acid was employed, and
when the reaction was carried out in 1,4-dioxane (120 °C, 10 h)
using K3PO4 as the base.11,12 No systematic trend was observed
for the relationship of yields and arylboronic acids employed.
The Suzuki reaction of 2 with arylboronic acids 3a–d,h–j
(1.0 equiv), in the presence of Pd(PPh3)4 (3 mol %), proceeded with
very good site-selectivity at position 10 and afforded the 10-aryl-
1,2,3,4-tetrahydro-9-trifluoromethyl-sulfonyloxy-anthracen-1-ones
5a–g in 70–88% yield (Scheme 3, Table 2).11,13 The products were
isolated in pure form after chromatography which was necessary
to remove a small amount of bis-coupled product detected in the
crude product mixture. During the optimization it proved to be
important to employ exactly 1.0 equiv of the arylboronic acid and
to carry out the reaction at 100 °C instead of 120 °C to avoid double
coupling.
The structures of all products were proved by 2D NMR experi-
ments (NOESY, HMBC). The structure of 5a was independently con-
firmed by X-ray crystal structure analysis (Fig. 2).15
Steric and electronic parameters can control the site-selectivity
of palladium(0) catalyzed cross-coupling reactions.16 The regiose-
The one-pot reaction of 2 with two different arylboronic acids,
which were sequentially added, afforded the 1,2,3,4-tetrahydro-
9,10-diarylanthracen-1-ones 6a–f, containing two different aryl
groups, in 70–80% yields (Scheme 4, Table 3).11,14 Following the
observations made during the optimization of the synthesis of
5a–g, the first step of the one-pot protocol was carried out at
100 °C and using exactly 1.0 equiv of the arylboronic acid.
OTf
OTf
ArB(OH)2
3a-d,h-j
i
OTf
O
Ar
O
5a-g
2
Scheme 3. Synthesis of 5a–g. Reagents and conditions: (i) 2 (1.0 equiv), 3a–d,h–j
(1.0 equiv), Pd(PPh3)4 (3 mol %), K3PO4 (2 equiv), 1,4-dioxane, 100 °C, 10 h.
Figure 2. Crystal structure of 5a.

394
G. A. Salman et al. / Tetrahedron Letters 52 (2011) 392–394
NMR (75.5 MHz, CDCl3): d = 21.6, 25.2, 39.6 (CH2), 118.5 (q, JF,C = 320.2 Hz, CF3),
carbon C-9
less sterically hindered
less electron deficient
118.6 (q, JF,C = 319.6 Hz, CF3), 121.5 (CH), 123.2 (q, JF,C = 1.4 Hz, CH), 123.9,
126.4 (C), 128.8 (CH), 129.8 (C), 131.3 (CH). 133.3, 140.4, 143.8 (C), 195.9 (CO).
2
~
v
IR (KBr):
= 2849, 2880, 2915, 2964 (w), 1697 (m), 1625, 1594, 1564, 1494,
OTf
1442 (w), 1422 (s), 1384, 1353, 1326, 1278 (w), 1205, 1185, 1129 (s), 1076,
1027 (m), 962 (s), 909 (m), 862 (s), 823, 809, 785 (w), 771 (m), 749 (s), 709 (m),
670 (s), 654, 644, 631 (w), 595 (s), 564, 532 (w) cmÀ1. GC/MS (EI, 70 eV): m/z
(%) = 492 (M+, 92), 359 (82), 295 (97), 253 (54). HRMS (EI, 70 eV): calcd for
C16H10O7S2F6: 491.97666; found: 491.976129.
OTf
O
11. General procedure for Suzuki–Miyaura reactions: A 1,4-dioxane solution (4–5 mL
per 0.3 mmol of 2), K3PO4 (1.5–2.0 equiv), Pd(PPh3)4 (3 mol % per cross-
coupling) and arylboronic acid 3 (1.0–1.1 equiv per cross-coupling) was stirred
at 100–120 °C for 10 h under argon atmosphere. After cooling to 20 °C, distilled
H2O was added. The organic and the aqueous layers were separated and the
latter was extracted with CH2Cl2. The combined organic layers were dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography.
1
2
carbon C-10
more sterically hindered
more electron-deficient
Scheme 5. Possible explanation for the site-selective reactions of 2.
12. Synthesis of 9,10-bis(4-methoxyphenyl)-3,4-dihydroanthracen-1(2H)-one (4a):
Starting with
2 (150 mg, 0.3 mmol), 4-methoxyphenylboronic acid 3a
lective formation of products 5a–g and 6a–f can be explained by
the fact that position 10 is electronically more deficient than posi-
tion 9 (Scheme 5). In addition, chelation of the catalyst to the car-
bonyl group might play a role.
In conclusion, the site-selectivity of Suzuki–Miyaura reactions
of the bis(triflate) of 1,2,3,4-tetrahydro-9,10-dihydroxyanthracen-
1-one is controlled by electronic parameters. The first attack occurs
at the electronically more deficient position 10.
(83 mg, 0.66 mmol), Pd(PPh3)4 (21 mg, 6 mol %), K3PO4 (191 mg, 0.9 mmol)
and 1,4-dioxane (5 mL), 4a was isolated as yellow solid (93 mg, 75%); mp 277–
278 °C. 1H NMR (300 MHz, CDCl3): d = 1.89–1.98 (m, 2H, CH2), 2.54 (t, 2H,
J = 6.7 Hz, CH2), 2.71 (t, 2H, J = 6.3 Hz, CH2), 3.82 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3), 6.95 (d, 2H, J = 8.7 Hz, ArH), 7.00 (d, 2H, J = 8.7 Hz, ArH), 7.08 (d, 2H,
J = 8.7 Hz, ArH), 7.15 (d, 2H, J = 8.7 Hz, ArH), 7.20–7.25 (m, 1H, ArH), 7.30 (td,
1H, J = 1.6, 8.5 Hz, ArH), 7.36–7.39 (m, 1H, ArH), 7.49–7.52 (m, 1H, ArH). 13C
NMR (62.9 MHz, CDCl3): d = 22.7, 29.4, 40.8 (CH2), 55.2, 55.3 (OCH3), 113.5,
114.1, 125.4, 126.3, 127.7, 128.6 (CH), 129.7 (C), 130.3 (CH), 131.1 (C), 131.2
(CH), 132.4, 132.5, 134.7, 137.4, 137.6, 141.6, 158.5, 158.9 (C), 200.2 (CO). IR
~
(KBr):
v = 3064, 3033, 3001, 2950, 2904, 2833 (w), 1689, 1607 (m), 1573, 1556
(w), 1509 (s), 1494, 1461, 1455, 1440, 1408, 1373, 1349, 1325, 1303 (w), 1283
(m), 1238 (s), 1172, 1154, 1104 (m), 1031 (s), 1004 (m), 959, 939, 927, 901, 865
(w), 834, 795, 767 (m), 728, 681, 648, 637, 623 (w), 589 (m), 542 (s) cmÀ1. GC/
MS (EI, 70 eV): m/z (%) = 408 (M+, 100), 279 (05), 349 (08), 321 (07). HRMS (EI,
70 eV): calcd for C28H23O3: 407.163709; found: 407.16417.
Acknowledgments
Financial support by the DAAD (scholarships for G.A.S. and for
A.M.), by the State of Pakistan (HEC scholarship for M.H.) and by
the State of Mecklenburg-Vorpommern (scholarship for M.S. and
M.H.) is gratefully acknowledged.
13. Synthesis
of
10-(4-tert-butylphenyl)-4-oxo-1,2,3,4-(tetrahydroanthracen-9-
yl)trifluoromethanesulfonate (5e): Starting with 2 (150 mg, 0.3 mmol), 4-tert-
butylphenylboronic acid (3h, 53 mg, 0.3 mmol), Pd(PPh3)4 (11 mg, 3 mol %),
K3PO4 (127 mg, 0.6 mmol) and 1,4-dioxane (5 mL), 5e was isolated as a yellow
solid (104 mg, 75%); mp 137–138 °C. 1H NMR (300 MHz, CDCl3): d = 1.35 (s, 9H,
3CH3), 2.10–2.14 (m, 2H, CH2), 2.60 (t, 2H, J = 7.3 Hz, CH2), 3.17 (t, 2H,
J = 6.4 Hz, CH2), 7.02 (d, 2H, J = 8.2 Hz, ArH), 7.34–7.5 (m, 4H, ArH), 7.59–7.64
(m, 1H, ArH), 8.03 (d, 1H, J = 8.8 Hz, ArH). 19F NMR (282.4 MHz, CDCl3):
d = À72.78. 13C NMR (62.9 MHz, CDCl3): d = 21.9, 25.4 (CH2), 31.5 (3CH3), 34.7
(C), 40.3 (CH2), 118.7 (q, JF,C = 320.6 Hz, CF3), 120.7, 125.0, 127.0 (CH), 128.3 (C),
128.4, 129.2 (CH), 129.3 (C), 129.8 (CH), 132.6, 133.7, 135.8, 141.1, 143.8, 150.0
~
References and notes
1. Römpp Lexikon Naturstoffe; Steglich, W., Fugmann, B., Lang-Fugmann, S., Eds.;
Thieme: Stuttgart, 1997.
2. Gill, M.; Gimenez, A.; Jhingran, A. G.; Palfreyman, A. R. Tetrahedron Lett. 1990,
31, 1203.
3. Review: Krohn, K. Angew. Chem. 1986, 98, 788; Angew. Chem., Int. Ed. Engl. 1986,
25, 790.
4. Roush, W. R.; Hartz, R. A.; Gustin, D. J. J. Am. Chem. Soc. 1999, 121, 1990.
5. Phifer, S. S.; Lee, D.; Seo, E. K.; Kim, N. C.; Graf, T. N.; Kroll, D. J.; Navarro, H. A.;
Izydore, R. A.; Jimenez, F.; Garcia, R.; Rose, W. C.; Fairchild, C. R.; Wild, R.;
Soejarto, D. D.; Farnsworth, N. R.; Kinghorn, A. D.; Oberlies, N. H.; Wall, M. E.;
Wani, M. C. J. Nat. Prod. 2007, 70, 954.
6. An, T. Y.; Hu, L. H.; Chen, R. M.; Chen, Z. L.; Li, J.; Shen, Q. Chin. Chem. Lett. 2003,
14, 489.
7. Lio, K.; Ramesh, N. G.; Okajima, A.; Higuchi, K.; Fujioka, H.; Akai, S.; Kita, Y. J.
Org. Chem. 2000, 65, 89.
(C), 197.5 (CO). IR (KBr):
v = 3077, 3047, 3027, 2961, 2903, 2865 (w), 1693 (m),
1617, 1591, 1563, 1515, 1494, 1476, 1462, 1439 (w), 1404 (m), 1361, 1320,
1292 (w), 1202, 1135 (s), 1076, 1051 (w), 1023, 965 (m), 931, 901 (w), 848, 832
(s), 800, 772 (w), 749 (s), 719, 698, 687 (w), 665 (m), 641, 619 (w), 582, 561 (m)
cmÀ1. GC/MS (EI, 70 eV): m/z (%) = 476 (M+, 4), 343 (14). HRMS (EI, 70 eV):
calcd for C25H23O4F3S: 476.12637; found: 476.124975.
14. Synthesis of 9-(4-tert-butylphenyl)-10-(4-methoxyphenyl)-3,4-dihydroanthracen-
1(2H)-one (6a): The synthesis of 6a was carried out as a one-pot reaction with
sequential addition of two different boronic acids. The first step (addition of
3a) was carried out at 100 °C (stirring for 10 h). The second step (addition of 3h
and of a fresh amount of catalyst) was carried out at 120 °C (stirring for 10 h).
Starting with 2 (150 mg, 0.3 mmol), 4-methoxyphenylboronic acid (3a, 46 mg,
0.3 mmol), Pd(PPh3)4 (2 Â 11 mg, 2 Â 3 mol %), K3PO4 (127 mg, 0.6 mmol), 1,4-
dioxane (5 mL), and 4-tert-butylphenylboronic acid (3h, 58 mg, 0.33 mmol), 6a
8. For reviews of cross-coupling reactions of polyhalogenated heterocycles, see:
(a) Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245; (b) Schnürch, M.;
Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur. J. Org. Chem.
2006, 3283.
was isolated as
a
yellow solid (102 mg, 77%); mp 272–274 °C. 1H NMR
(300 MHz, CDCl3): d = 1.36 (s, 9H, 3CH3), 1.90–1.98 (m, 2H, CH2), 2.55 (t, 2H,
J = 6.7 Hz, CH2), 2.71 (t, 2H, J = 6.7 Hz, CH2), 3.83 (s, 3H, O CH3), 6.96 (d, 2H,
J = 8.8 Hz, ArH), 7.10 (d, 2H, J = 8.9 Hz, ArH), 7.16 (d, 2H, J = 8.9 Hz, ArH), 7.20–
7.38 (m, 3H, ArH), 7.45–7.53 (m, 3H, ArH). 13C NMR (75–5 MHz, CDCl3):
d = 22.7, 29.4 (CH2), 31.5 (3CH3), 34.7 (C), 40.9 (CH2), 55.3 (OCH3), 113.5, 125.4,
125.5, 126.4, 127.7, 128.5, 129.8, 130.3 (CH), 132.5, 132.6, 134.6, 136.0, 137.4,
~
9. For Suzuki-Miyaura reactions of bis(triflates) of benzene derivatives and other
arenes, see, for example: (a) Takeuchi, M.; Tuihiji, T.; Nishimura, J. J. Org. Chem.
1993, 58, 7388; (b) Sugiura, H.; Nigorikawa, Y.; Saiki, Y.; Nakamura, K.;
Yamaguchi, M. J. Am. Chem. Soc. 2004, 126, 14858; (c) Akimoto, K.; Suzuki, H.;
Kondo, Y.; Endo, K.; Akiba, U.; Aoyama, Y.; Hamada, F. Tetrahedron 2007, 63,
6887; (d) Akimoto, K.; Kondo, Y.; Endo, K.; Yamada, M.; Aoyama, Y.; Hamada, F.
Tetrahedron Lett. 2008, 49, 7361; (e) Hosokawa, S.; Fumiyama, H.; Fukuda, H.;
Fukuda, T.; Seki, M.; Tatsuta, K. Tetrahedron Lett. 2007, 48, 7305; (f) Nawaz, M.;
Farooq Ibad, M.; Obaid-Ur-Rahman, A.; Khera, R. A.; Villinger, A.; Langer, P.
Synlett 2010, 150; (g) Mahal, A.; Villinger, A.; Langer, P. Synlett 2010, 1085.
10. Synthesis of 1-oxo-1,2,3,4-tetrahydroanthracene-9,10-diyl-bis(trifluoromethane-
sulfonate (2). To a solution of 1 (2.0 g, 8.8 mmol) in CH2Cl2 (88 mL) was added
pyridine (2.8 mL, 35.0 mmol) at 20 °C under an argon atmosphere. After
stirring for 10 min, Tf2O (3.5 mL, 21 mmol) was added at À78 °C. The mixture
was allowed to warm to 20 °C and was stirred overnight. The reaction mixture
was filtered and the filtrate was concentrated in vacuo. The residue was
purified by chromatography (flash silica gel, heptanes–EtOAc) without prior
aqueous work up to give 2 as a yellow solid (3.67 g, 85%), mp 162–164. 1H NMR
(300 MHz, CDCl3): d = 2.10–2.18 (m, 2H, CH2), 2.76 (t, 2H, J = 6.9 Hz, CH2), 3.15
(t, 2H, J = 6.4 Hz, CH2), 7.65–7.79 (m, 2H, ArH), 8.05 (d, 1H, J = 8.5 Hz, ArH), 8.18
(d, 1H, J = 8.5 Hz, ArH). 19F NMR (282.4 MHz, CDCl3): d = À72.56, À72.55. 13C
137.8, 141.6, 150.3, 158.5 (C), 200.2 (CO). IR (KBr):
v = 3064, 3042, 3000, 2956,
2899, 2865, 2833, 2252, 2142 (w), 1689 (m), 1608, 1573, 1553 (w), 1510 (m),
1493, 1459, 1440, 1410, 1395, 1373, 1365, 1349, 1327, 1315, 1304, 1284, 1269
(w), 1239 (s), 1224, 1174 (m), 1158, 1131, 1116, 1108, 1073 (w), 1030 (m),
1006, 971, 938, 926 (w), 912, 837 (m), 817, 803, 796 (w), 765, 726 (s), 692, 676,
646, 638, 619, 586 (w), 561, 543 (m) cmÀ1. GC/MS (EI, 70 eV): m/z (%) = 434
(M+, 100), 419 (11), 349 (14). HRMS (ESI+): calcd for C31H31O2: [M+H]+:
435.2319; found: 435.2312.
15. CCDC-800257 contains the supplementary crystallographic data for this Letter.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
16. For a simple guide for the prediction of the site-selectivity of palladium(0)
catalyzed cross-coupling reactions based on the 1H NMR chemical shift values,
see: Handy, S. T.; Zhang, Y. Chem. Commun. 2006, 299.